EP0806943B1 - Valaciclovir tablets containing colloidal silicon dioxide - Google Patents

Valaciclovir tablets containing colloidal silicon dioxide Download PDF

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Publication number
EP0806943B1
EP0806943B1 EP96900626A EP96900626A EP0806943B1 EP 0806943 B1 EP0806943 B1 EP 0806943B1 EP 96900626 A EP96900626 A EP 96900626A EP 96900626 A EP96900626 A EP 96900626A EP 0806943 B1 EP0806943 B1 EP 0806943B1
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Prior art keywords
tablet
valaciclovir
silicon dioxide
lubricant
colloidal silicon
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German (de)
English (en)
French (fr)
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EP0806943A1 (en
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Barry Howard Carter
Lloyd Gary Tillman
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Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • This invention relates to a tablet of the antiviral drug valaciclovir.
  • the compound 9-[(2-hydroxyethoxy)methyl]guanine otherwise known as acyclovir, possesses potent antiviral activity and is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses (see, for example, Schaeffer et al, Nature, 272, 583-585 (1978), UK-A-1523865, US-A-4,199,574).
  • acyclovir is poorly absorbed from the gastro-intestinal tract upon oral administration and this low bioavailability means that multiple high doses of oral drug may need to be administered, especially for the treatment of less sensitive viruses or infections in order to achieve and maintain effective anti-viral levels in the plasma.
  • valaciclovir The L-valine ester of acyclovir (2-[(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy]ethyl L-valinate) (herein referred to as valaciclovir) has been shown to possess much improved bioavailability whilst retaining the anti-viral properties of acyclovir.
  • a preferred form of this compound is its hydrochloride salt which is herein referred to as valaciclovir hydrochloride.
  • Valaciclovir and its salts including the hydrochloride salt are disclosed in US-A-4,957,924 (see particular example 1B), EP-B-0308065 (see particularly example 1B) and Beauchamp et al, Antiviral Chemistry and Chemotherapy, 3(3), 157-164 (1992) (see particularly page 162 column 1). Tablets of valaciclovir are also generally disclosed in the US-A-4,957,924 and EP-A-0308065.
  • valaciclovir has 'adhesive' properties in that it can stick to tablet dies and therefore needs to be efficiently lubricated. It is difficult therefore to reduce the proportion of lubricant without causing the tablets to stick.
  • the disintegration time of the valaciclovir tablet is also quite long and therefore any possible solution to the hardness and friability problem should not have a substantial deleterious effect on either the disintegration time or lubrication (as measured by the ejection force) of the tablet formulation.
  • silica powder is added to ibuprofen tablets as an antiadherent to prevent the formulation sticking to the punch faces (a particular problem associated with ibuprofen in high humidity climates, such as China). Hardness and disintegration time were said to improve, but there is no mention of the effect on ejection force. Microcellulose was also used.
  • J. Pharm. Pharmacol. 1985, 37:193-195 relates to a 500 mg paracetamol tablet in which various excipients including Aerosil (i.e. colloidal silicon dioxide) were added.
  • Aerosil i.e. colloidal silicon dioxide
  • the tablet did not, however, contain an extragranular cellulosic filler.
  • the hardness of the tablet should be such that it not only has an acceptable crushing force (as measured by the kP value), but also that the tablet does not break during tumbling.
  • a tablet comprising at least 50% w/w valaciclovir or a salt thereof present within the granules of the tablet, a cellulosic filler, a binding agent, a lubricant, and 0.05% to 3% w/w colloidal silicon dioxide, the lubricant, colloidal silicon dioxide and at least a portion of the cellulosic filler being present extragranularly, wherein the friability of the tablet does not exceed 1%, the hardness is at least 9kP and the ejection force does not exceed 1000 Newtons.
  • a tablet of this formulation containing 0.05% to 3% w/w colloidal silicon dioxide and a cellulosic filler is robust, and has a substantially improved friability and hardness. Furthermore such improved properties are achieved while still retaining a satisfactory disintegration time and lubrication properties, even when the formulation is blended under high shear.
  • An excellent tablet providing acyclovir in a highly bioavailable form is thus provided by virtue of the invention.
  • the disintegration time of the tablet is not more than 30 minutes, more preferably not more than 25 minutes, and most preferably not more than 20 minutes.
  • the ejection force should not be more than 1000N, preferably not more than 800N, more preferably still not more than 500N for tablets compressed at 10 to 30 kN, preferably 10 to 20 kN.
  • Valaciclovir or a salt thereof are hereinafter referred to generally as the 'active ingredient' or 'drug'.
  • colloidal silicon dioxide in its monograph
  • colloidal silicon dioxide in its monograph
  • a submicroscopic fumed silica prepared by the vapour phase hydrolysis of a silica compound.
  • the colloidal silicon dioxide is present in amounts of 0.05% to 1% w/w of the total formulation, more preferably at 0.1% to 1% w/w, and most preferably 0.1% to 0.5%.
  • Aerosil trade mark
  • Cab-o-Sil trade mark
  • the content of drug in the tablet is at least 50% w/w, preferably 60% to 90% w/w, more preferably still 65% w/w to 85% w/w and most preferably about 80% w/w.
  • the (tapped) bulk density of the drug is 0.1 to 0.9 g/cc, more preferably 0.3 to 0.7 g/cc, more preferably still 0.34 to 0.66 g/cc, and most preferably 0.4 to 0.6g/cc.
  • the drug is valaciclovir hydrochloride, preferably being of an anhydrous crystalline form including substantially a d-spacing pattern (derived from X-ray powder diffraction) as follows: d spacing pattern (in Angstroms): 10.20 ⁇ 0.08, 8.10 ⁇ 0.06, 7.27 ⁇ 0.06, 6.08 ⁇ 0.05, 5.83 ⁇ 0.03, 5.37 ⁇ 0.02, 5.23 ⁇ 0.02, 4.89 ⁇ 0.02, 4.42 ⁇ 0.02, 4.06 ⁇ 0.02, 3.71 ⁇ 0.02, 3.39 ⁇ 0.02, 3.32 ⁇ 0.02, 2.91 ⁇ 0.02, 2.77 ⁇ 0.02.
  • d-spacing pattern derived from X-ray powder diffraction
  • anhydrous crystalline form a crystalline form having substantially the same X-ray powder diffraction pattern as shown in figures 1 to 3, or having substantially the same d spacing pattern as defined above.
  • the crystal form purity in any such drug lot of anhydrous crystalline valaciclovir hydrochloride used for valaciclovir tablets is as least 70%, more preferably at least 80%, more preferably still at least 90% and most preferably at least 95% anhydrous crystalline valaciclovir hydrochloride (as characterised above).
  • any drug lot of anhydrous crystalline valaciclovir hydrochloride contains no more than 3% w/w, more preferably no more than 2% w/w, more preferably still not more than 1 % w/w and most preferably not more than 0.5 % w/w water of hydration.
  • the filler is a cellulosic filler and is at least partly present extragranularly, which mitigates stress cracking of the tablet.
  • a tablet formulation of the invention including colloidal silicon dioxide and extragranular cellulosic filler (such as microcrystalline cellulose) appears to have a synergistic effect and is particularly good and robust in that tablets of valaciclovir can consistently be made to an acceptable hardness without introducing stress cracks even under a high compression force.
  • a tablet comprising at least 50% w/w valaciclovir or a salt thereof, a binding agent, a lubricant, 0.05 to 3% w/w colloidal silicon dioxide, and 3 to 30% of a cellulosic filler; wherein the valaciclovir or salt thereof is present within the granules of the tablet, the lubricant, colloidal silicon dioxide, and at least a portion of the cellulosic filler is present extragranularly; wherein the friability of the tablet does not exceed 1%, the hardness is at least 9kP, and the ejection force does not exceed 1000N.
  • the cellulosic filler is microcrystalline cellulose (e.g. Avicel); and is preferably present at 5 to 15% w/w, most preferably about 10% w/w.
  • the particle size of the cellulosic filler is preferably 20 to 300 ⁇ m, more preferably 30 to 200 ⁇ m, and most preferably 50 to 100 ⁇ m.
  • the binding agent serves, for example, to bind the primary and secondary particles together and improve tablet hardness.
  • the binding agent is present in an amount of 1% to 5% w/w, more preferably at 2% to 4% w/w, and is suitably a non-starch based binder such as methylcellulose or most preferably povidone.
  • the grade of povidone is advantageously K30 and most preferably K90.
  • the binding agent such as the povidone
  • the granulating solvent such as water
  • the lubricant is suitably present in an amount of 0.1% to 2.0% w/w, preferably 0.1% to 1.0% w/w.
  • lubricants such as talc or sodium lauryl sulphate are suitable, preferably the lubricant is a stearate derivative, more preferably an alkaline earth metal stearate, such as magnesium stearate.
  • the above amounts apply to the stearate, and they are ideally present in amount of 0.3% to 0.6% w/w.
  • a disintegrating agent is present in the tablet formulation, suitably in an amount of 0.5 to 20% w/w, more preferably at 0.5% to 7.0% w/w.
  • the disintegrating agent is advantageously present within the granules of the tablet and can be added before or after the binding agent.
  • Clays such as kaolin, bentonite or Veegum (trademark), and celluloses such as microcrystalline cellulose or croscarmellose sodium e.g. Ac-Di-Sol (trademark) may be used as disintegrants.
  • a non-ionic disintegrant such as crospovidone is used.
  • the crospovidone is present at 0.5% to 7.0% w/w, more preferably 2 to 5% w/w, and preferably a portion is present intragranularly.
  • a further aspect of the invention provides a process for preparing a tablet comprising at least 50% w/w valaciclovir or a salt thereof, a binding agent, a cellulosic filler, a lubricant, and 0.05 to 3.0% w/w colloidal silicon dioxide; wherein the hardness of the tablet is at least 9 kP, the friability is not more than 1%, and the ejection force is not more than 1000N; said process comprising forming granules which include valaciclovir or a salt thereof and then blending the lubricant, colloidal silicon dioxide and at least a portion of the cellulosic filler with said granules.
  • Preferably said process comprises forming granules by mixing said valaciclovir or salt, optionally a binding agent or a portion thereof, and optionally a portion of cellulosic filler; granulating with a granulating solution to form granules or dissolving the binding agent or a portion in the granulating solution before adding to valaciclovir; drying the granules; blending the granules with the lubricant, colloidal silicon dioxide, and cellulosic filler or a portion thereof; and then compressing the blended mixture to form a tablet.
  • a preferred aspect of the invention provides a process for preparing a tablet comprising at least 50% w/w valaciclovir or a salt thereof, a binding agent, a lubricant, 0.05 to 3% w/w colloidal silicon dioxide, and 3 to 30% w/w of a cellulosic filler; wherein the hardness of the tablet is at least 9kP, the friability is not more than 1%, and the ejection force is not more than 1000N; said process comprising forming granules by mixing the valaciclovir or salt, optional binding agent or a portion thereof, and optionally a portion of cellulosic filler; granulating with a granulating solution to form granules or dissolving the binding agent or a portion thereof in the granulating solution before adding to valaciclovir; drying the granules; blending the granules with the lubricant, colloidal silicon dioxide, and at least a portion of the cellulosic fill
  • the colloidal silicon dioxide can be first blended with the lubricant, preferably a stearate derivative (e.g. magnesium stearate) before blending with the granules or it can be added separately from the lubricant.
  • a stearate derivative e.g. magnesium stearate
  • the ratio of stearate to colloidal silicon dioxide is 1:1 to 10:1, more preferable 1:1 to 3:1.
  • the present Invention also provides a tablet (as described above) for use In medical therapy, e.g. in the treatment of a viral disease in an animal, e.g. a mammal such as a human.
  • the compound is especially useful for the treatment of diseases caused by various DNA viruses, such as herpes infections, for example, herpes simplex 1 and 2, varicella zoster, cytomegalovirus, Epstein-Barr viruses or human herpes virus-6 (HHV-6) as well as diseases caused by hepatitis B.
  • the active compound can also be used for the treatment of papilloma or wart virus infections and, may furthermore be administered in combination with other therapeutic agents, for example with zidovudine, to treat retroviral associated infections in particular HIV infections.
  • the active compound can be administered to other animals for treatment of viral diseases, e.g. to other mammals.
  • the present invention also provides the use of the active compound in the preparation of a tablet of the invention for the treatment of a viral infection.
  • a tablet of the invention may be administered by any route appropriate to the condition to be treated, but the preferred route of administration is oral.
  • tablets generally are included within the scope of the invention, for example a dispersible tablet or chewable tablet, preferably the tablet is a swallowable tablet, most preferably a film-coated swallowable tablet. It will be appreciated however, that the preferred route may vary with, for example, the condition of the recipient.
  • a suitable effective dose will be in the range 1 to 150 mg per kilogram bodyweight of recipient per day, preferably in the range 5 to 120 mg per kilogram bodyweight per day (Unless otherwise indicated, all weights of the active ingredient are calculated with respect to the free base valaciclovir).
  • the desired dose is preferably presented as one, two, three or four or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 50 to 2000 mg, preferably 250, 500, 1000 or 2000mg of active ingredient per unit dose form.
  • herpes simplex virus types 1 and 2 infection - total daily dose of 1 or 2 g administered at 500mg twice a day or lg twice a day for 5 to 10 days; suppression of herpes simplex virus types 1 and 2 infections:- total daily dose 250mg to 1g for one to ten years (depending on the patient); treatment of varicella zoster virus infections (for example shingles):- daily dose about 3g administered at 1g three times a day for seven days; suppression of cytomegalovirus infections:- total daily dose about 8g administered at 2g 4 times a day.
  • this daily dose is administered for three to six months for the period at risk; and for HIV positive patients said daily dose is administered as usually indicated for improving quality of life, for example for two years or more.
  • valaciclovir can be used in the effective suppression of recurrent genital herpes at a once daily dose of from 200 mg to 1000 mg for an effective treatment period.
  • the most likely daily dosages are 250 mg, 500 mg or 1000 mg.
  • Valaciclovir hydrochloride was made as described below:
  • the X-ray powder diffraction patterns of the product of example 1B are shown in Figure 1 of the accompanying drawings.
  • the d spacings and further X-ray diffraction data are shown in Table 1.
  • the powder sample used to produce the above X-ray diffraction data was prepared by an equivalent method as the powder sample used to produce the X-ray diffraction data of table 2 (described hereinafter) except that for the above data the following preparation was used to prepare the powder sample.
  • the sample was prepared by milling 1 g of sample in a plastic cup using two acrylic balls for 5 minutes with a Chemplex Spectromill. The samples were then back packed against a glass slide to a depth of 2 mm.
  • the X-ray diffraction scan was obtained using a Scintag PADV diffractometer in the step scan mode at 0.02° per step and a 10 second count per step. The sample holder was spun at 1 rotation per second during the scan. Additional setting as described below.
  • X-ray generator 45 kV, 40 mA Radiation Copper K alpha radiation Fixed divergent slit 1 mm Incident scatter slit 2 mm Diffracted scatter slit 0.5 mm Receiving slit 0.3 mm Goniometer radius 235 mm Detector Scintillation with a graphite monochromator.
  • the peak intensities are reported as absolute counts of the peak top.
  • the intensity units on the X-ray diffraction plot are counts/sec.
  • the peak intensities in the table have been corrected for background and copper K alpha II X-ray wavelength contribution.
  • reaction mixture was stirred for a further 1 hour then a second charge of formic acid made (20.88 ml) and the mixture filtered to remove the catalyst. The filtrate was treated with concentrated hydrochloric acid (38.56 ml) and the resultant mixture was concentrated under vacuum.
  • Acetone (1480 ml) was then added over 15 minutes and the suspension stirred for 1 hour before filtering off the product. The solid was then slurried with acetone (ca. 500 ml), refiltered and dried at 60°C in vacuo to give the title compound (137.75 g : 87.6%).
  • the diffraction patterns of the product of example 2B were generated on a Phillips PW1800 Automatic X-ray Powder Diffractometer using a scan of 2 to 45 2 ⁇ with step intervals of 0.02 degrees and an integration time of 4 seconds per step.
  • the powder sample was prepared as follows:
  • a 1 gram portion of valaciclovir hydrochloride was transferred to a Retsch 10 ml polystyrol container ref 31-762 containing 2 acrylic balls ref 26-253 and was then ground to a very fine powder using a Retsch MM2 miser mill set at 100% power for five minutes.
  • the ground powder was back loaded into a Philips PW1811/10 sample holder which had been placed inverted on a perfectly smooth surface (e.g. that afforded by a glass plate or a highly polished metal sheet).
  • the powder was then packed into the holder and further powder added and packed until the holder was full.
  • a Philips PW 1811 00 bottom plate was then clamped into the holder and the entire assembly was then inverted before removing the glass/metal plate in an upwards direction to reveal the smooth sample surface which was flush with that of the holder.
  • Example 8 9 Ingredients mg/tablet w/w mg/tablet w/w valaciclovir hydrochloride 615 65.80 615 65.74 lactose 205 21.93 205 21.91 microcrystallinecellulose (Avicel PH101) (intragranular) 75 8.02 75 8.02 povidone K30 18 1.93 18 1.92 crospovidone (intragranular) 18 1.93 18 1.92 colloidal silicon dioxide (Aerosil 200) 0.0 0.0 0.9 0.10 magnesium stearate 3.6 0.39 3.6 0.38 TOTAL WEIGHT 934.6 100.0 935.5 100
  • Example 10 11 Ingredients mg/tablet w/w mg/tablet w/w valaciclovir hydrochloride 580 81.01 580 82.60 lactose - - - - microcrystalline cellulose (Avicel PH101) (intragranular) 70 9.78 - - microcrystalline cellulose
  • Step 1 The following ingredients as shown were sifted with a hand screen. 30 Mesh (600 ⁇ m) valaciclovir hydrochloride 5.289 kg lactose 1.763 kg microcrystalline Cellulose 0.6450 kg povidone K30 0.1548 kg crospovidone 0.1548 kg 60 Mesh (250 ⁇ m) magnesium stearate 0.03096 kg colloidal silicon dioxide (CSD) 0.002598 kg
  • Examples 10 and 11 were manufactured in a substantially similar manner to Examples 9 and 10 with the following exceptions.
  • Example 4 which lacks colloidal silicon dioxide and has microcrystalline cellulose intragranularly broke in half during tumbling, to simulate film coating conditions. The hardness of the tablet is therefore totally unacceptable.
  • colloidal silicon dioxide was added (Example 3) the tablet surprisingly did not break and furthermore the disintegration time and ejection force increased by substantially less than would be expected.
  • Example 5 The tablets of Examples 5 and 6, like that of Example 3, developed stress cracks after heating.
  • Example 3 there was present colloidal silicon dioxide and intragranular microcrystalline cellulose; in Example 5 the microcrystalline cellulose was also intragranular, but there was no colloidal silicon dioxide; and in Example 6 again there was no colloidal silicon dioxide, but the microcrystalline cellulose was extragranular.
  • Example 8a the hardness value is very low and the friability fails the US Pharmacopoeia (USP) limit of 1%. Even at the very high compression force used in Example 8b), the friability still fails the USP test.
  • USP US Pharmacopoeia
  • Example 9a and b In contrast on the addition of about 0.1% w/w of colloidal silicon dioxide (in Example 9a and b), hardness and friability have dramatically improved. Furthermore the ejection force, which was good before the addition of colloidal silicon dioxide is still good, and in fact actually improved on its addition. The disintegration time of the tablets of Example 9 is also very satisfactory.
  • Example 11 when the formulation of Example 11 is repeated incorporating colloidal silicon dioxide in amounts ranging from 0.05 to 3% w/w, excellent tablets can be consistently produced having a high hardness and low friability value, substantially free of stress-cracks.
  • the robust tablet formulation of the invention therefore can consistently provide valaciclovir tablets having excellent handling characteristics which are suitable for film coating and which still have an adequate lubricating and disintegration time.

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EP96900626A 1995-01-20 1996-01-19 Valaciclovir tablets containing colloidal silicon dioxide Expired - Lifetime EP0806943B1 (en)

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SI9630193T SI0806943T1 (en) 1995-01-20 1996-01-19 Valaciclovir tablets containing colloidal silicon dioxide

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GB9501127 1995-01-20
GBGB9501127.6A GB9501127D0 (en) 1995-01-20 1995-01-20 Tablet
PCT/GB1996/000111 WO1996022082A1 (en) 1995-01-20 1996-01-19 Valaciclovir tablets containing colloidal silicon dioxide

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EP0806943A1 EP0806943A1 (en) 1997-11-19
EP0806943B1 true EP0806943B1 (en) 2000-03-15

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AP9701057A0 (en) 1997-10-31
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IL116830A (en) 2000-02-29
KR19980701524A (ko) 1998-05-15
EP0806943A1 (en) 1997-11-19
CN1313081C (zh) 2007-05-02
NO973327D0 (no) 1997-07-18
FI973062A0 (fi) 1997-07-18
CZ296514B6 (cs) 2006-03-15
HUP9801872A3 (en) 2001-02-28
NO973327L (no) 1997-09-16
CN1131026C (zh) 2003-12-17
SK282030B6 (sk) 2001-10-08
CN1494898A (zh) 2004-05-12
MX9705459A (es) 1997-10-31
JPH10512564A (ja) 1998-12-02
UY25778A1 (es) 2000-08-21
DE69607146T2 (de) 2000-09-21
KR100412298B1 (ko) 2004-04-21
HU226131B1 (en) 2008-05-28
UY25774A1 (es) 2000-10-31
UA68325C2 (en) 2004-08-16
BR9606769A (pt) 1997-12-30
WO1996022082A1 (en) 1996-07-25
FI973062A (fi) 1997-09-18
CA2210891C (en) 2009-05-19
US5879706A (en) 1999-03-09
IN181318B (zh) 1998-05-09
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AP666A (en) 1998-08-24
MY126346A (en) 2006-09-29
GB9501127D0 (en) 1995-03-08
RO118175B1 (ro) 2003-03-28
ATE190483T1 (de) 2000-04-15
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